【Publications】GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis

October 26 2023

Lab: Hitoshi Takizawa

Paper information

Tile:

GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis

Yu Wei Zhang, Talia Velasco-Hernandez, Julian Mess, Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Nadine Obier, Nikolaos Karantzelis, Jasmin Rettkowski, Katharina Schönberger, Noémie Karabacz, Karin Jäcklein, Tatsuya Morishima, Juan Luis Trincado, Paola Romecin, Alba Martinez-Moreno, Hitoshi Takizawa, Khalid Shoumariyeh, Simon Renders, Robert Zeiser, Heike L. Pahl, François Béliveau, Josée Hébert, Bernhard Lehnertz, Guy Sauvageau, Pablo Menendez, Nina Cabezas-Wallscheid

Blood Advances 2023/8/28  doi: 10.1182/bloodadvances.2023010460

Highlights

• Gprc5c drives AML progression through regulating BCAAs transporters, SLC7A5 and SLC43A1

• Inhibition of SLC7A5 using JPH203 elicits strong anti-leukemic effects in AML, effect, strengthened by venetoclax and azacitidine treatment

Abstract:

Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong anti-leukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow (BM) cells. This anti-leukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.

Graphical abstract